This research project is designed to discover the mechanisms by which uric acid crosses cell and tissue barriers in man. In order to facilitate this objective, the work has been divided into five major parts. In part 1, the in vitro binding of uric acid to serum proteins will be investigated with particular emphasis on the possible role of metallic ions in such binding. The second part will focus on reabsorption of uric acid in the kidney and will consist primarily of studies in the Dalmatian coach hound which lacks such a reabsorptive system. Secretion of uric acid by the kidney tubule will be studied in the third part in which special emphasis will be placed on studies of a unique patient who does not reabsorb uric acid, thus isolating the secretory system and facilitating its study. Part four is devoted to isotopic studies of uric acid metabolism in man and experimental animals using a much improved system which was developed in this laboratory. In the last section, the rate at which uric acid and other small molecules cross capillary walls will be investigated by a unique technique developed under this grant. The method involves studies of molecular exchange across the lining of normal and diseased human knees, and is a new contribution to the study of capillary permeability. All of these approaches are designed to increase our understanding of hyperuricemia in man. Hyperuricemia is a frequent finding and leads directly to gout in 2 per cent of adult American men.